{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T22:19:05Z","timestamp":1759961945277,"version":"3.41.2"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,2,18]],"date-time":"2022-02-18T00:00:00Z","timestamp":1645142400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:p>Seasonal influenza virus epidemics result in severe illness, and occasionally influenza pandemics cause significant morbidity and mortality, although vaccines and anti-influenza virus drugs are available. By screening an in-house library, we identified methylthio-formycin (SMeFM), an adenosine analog, as a potent inhibitor of influenza virus propagation. SMeFM inhibited the propagation of influenza A and B viruses (IC<jats:sub>50<\/jats:sub>: 34.1 and 37.9 nM, respectively) and viruses showing reduced susceptibility to baloxavir and neuraminidase inhibitors but not T-705 (Favipiravir). However, the combination of T-705 and SMeFM inhibited the propagation of the influenza virus not in an antagonistic but in a slightly synergistic manner, suggesting that SMeFM has targets distinct from that of T-705. SMeFM induced A-to-C transversion mutations in virus genome RNA, and SMeFM triphosphate did not inhibit <jats:italic>in vitro<\/jats:italic> viral RNA synthesis. Our results show that SMeFM inhibits the propagation of the influenza virus by a mechanism different from that of T-705 and is a potential drug candidate to develop for anti-influenza drug.<\/jats:p>","DOI":"10.3389\/fmicb.2022.802671","type":"journal-article","created":{"date-parts":[[2022,2,18]],"date-time":"2022-02-18T04:34:27Z","timestamp":1645158867000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Anti-influenza Virus Activity of Methylthio-Formycin Distinct From That of T-705"],"prefix":"10.3389","volume":"13","author":[{"given":"Naoki","family":"Takizawa","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hisashi","family":"Takada","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maya","family":"Umekita","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masayuki","family":"Igarashi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshiaki","family":"Takahashi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,2,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"3741","DOI":"10.1128\/JVI.02346-12","article-title":"T-705 (Favipiravir) induces lethal mutagenesis in influenza A H1N1 viruses in vitro.","volume":"87","author":"Baranovich","year":"2013","journal-title":"J. Virol."},{"key":"B2","doi-asserted-by":"crossref","first-page":"2114","DOI":"10.1093\/bioinformatics\/btu170","article-title":"Trimmomatic: a flexible trimmer for Illumina sequence data.","volume":"30","author":"Bolger","year":"2014","journal-title":"Bioinformatics"},{"key":"B3","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1016\/0006-2952(73)90269-4","article-title":"Inhibition of purine biosynthesis de novo in sarcoma 180 ascites cells by mercapto and seleno purine analogs.","volume":"22","author":"Crabtree","year":"1973","journal-title":"Biochem. Pharmacol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"862","DOI":"10.1126\/science.144.3620.862","article-title":"Antiviral activity of 1-adamantanamine (amantadine).","volume":"144","author":"Davies","year":"1964","journal-title":"Science"},{"key":"B5","doi-asserted-by":"publisher","first-page":"2301","DOI":"10.1021\/acs.jmedchem.5b01157","article-title":"C-nucleosides to be revisited.","volume":"59","author":"De Clercq","year":"2015","journal-title":"J. Med. Chem."},{"key":"B6","doi-asserted-by":"crossref","first-page":"91","DOI":"10.2174\/1389200219666180821094502","article-title":"The impact of carboxylesterases in drug metabolism and pharmacokinetics.","volume":"20","author":"Di","year":"2019","journal-title":"Curr. Drug Metab."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1949","DOI":"10.1128\/AAC.41.9.1949","article-title":"Penetration of GS4071, a novel influenza neuraminidase inhibitor, into rat bronchoalveolar lining fluid following oral administration of the prodrug GS4104.","volume":"41","author":"Eisenberg","year":"1997","journal-title":"Antimicrob. Agents Chemother."},{"key":"B8","doi-asserted-by":"publisher","first-page":"946","DOI":"10.1128\/AAC.11.6.946","article-title":"Inhibition of influenza virus ribonucleic acid polymerase by ribavirin triphosphate.","volume":"11","author":"Eriksson","year":"1977","journal-title":"Antimicrob. Agents Chemother."},{"journal-title":"Nitrogen-containing heterocyclic carboxamide derivatives or salts thereof and antiviral agents comprising the same","year":"","author":"Furuta","key":"B9"},{"key":"B10","doi-asserted-by":"publisher","first-page":"977","DOI":"10.1128\/AAC.46.4.977","article-title":"In vitro and in vivo activities of anti-influenza virus compound T-705.","volume":"46","author":"Furuta","year":"","journal-title":"Antimicrob. Agents Chemother."},{"key":"B11","doi-asserted-by":"publisher","first-page":"981","DOI":"10.1128\/AAC.49.3.981-986.2005","article-title":"Mechanism of action of T-705 against influenza virus.","volume":"49","author":"Furuta","year":"2005","journal-title":"Antimicrob. Agents Chemother."},{"key":"B12","doi-asserted-by":"publisher","first-page":"11613","DOI":"10.1073\/pnas.1811345115","article-title":"The mechanism of resistance to favipiravir in influenza.","volume":"115","author":"Goldhill","year":"2018","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B13","doi-asserted-by":"publisher","first-page":"913","DOI":"10.1056\/NEJMoa1716197","article-title":"Baloxavir marboxil for uncomplicated influenza in adults and adolescents.","volume":"379","author":"Hayden","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"B14","first-page":"49","article-title":"Studies on the antiviral activity of formycin.","volume":"20","author":"Ishida","year":"1967","journal-title":"J. Antibiot."},{"key":"B15","doi-asserted-by":"publisher","first-page":"e68347","DOI":"10.1371\/journal.pone.0068347","article-title":"The ambiguous base-pairing and high substrate efficiency of T-705 (favipiravir) Ribofuranosyl 5\u2019-triphosphate towards influenza A virus polymerase.","volume":"8","author":"Jin","year":"2013","journal-title":"PLoS One"},{"key":"B16","doi-asserted-by":"publisher","first-page":"6197","DOI":"10.1128\/JVI.00277-11","article-title":"Replication-coupled and host factor-mediated encapsidation of the influenza virus genome by viral nucleoprotein.","volume":"85","author":"Kawaguchi","year":"2011","journal-title":"J. Virol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"681","DOI":"10.1021\/ja963036t","article-title":"Influenza neuraminidase inhibitors possessing a novel hydrophobic interaction in the enzyme active site: design, synthesis, and structural analysis of carbocyclic sialic acid analogues with potent anti-influenza activity.","volume":"119","author":"Kim","year":"1997","journal-title":"J. Am. Chem. Soc."},{"key":"B18","doi-asserted-by":"publisher","first-page":"468","DOI":"10.7164\/antibiotics.21.468","article-title":"Structural requirements for formycin activity.","volume":"21","author":"Kunimoto","year":"1968","journal-title":"J. Antibiot."},{"key":"B19","doi-asserted-by":"publisher","first-page":"498","DOI":"10.1128\/AAC.12.4.498","article-title":"Double-blind evaluation of oral ribavirin (virazole) in experimental influenza A virus infection in volunteers.","volume":"12","author":"Magnussen","year":"1977","journal-title":"Antimicrob. Agents Chemother."},{"key":"B20","doi-asserted-by":"publisher","first-page":"2293","DOI":"10.1056\/NEJMoa1910993","article-title":"A randomized, controlled trial of ebola virus disease therapeutics.","volume":"381","author":"Mulangu","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1128\/mBio.01248-16.Editor","article-title":"Complete and incomplete genome packaging of influenza A and B viruses.","volume":"7","author":"Nakatsu","year":"2016","journal-title":"mBio"},{"key":"B22","doi-asserted-by":"publisher","first-page":"9345","DOI":"10.1073\/pnas.96.16.9345","article-title":"Generation of influenza A viruses entirely from cloned cDNAs.","volume":"96","author":"Neumann","year":"1999","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B23","doi-asserted-by":"publisher","first-page":"490","DOI":"10.1038\/nature04378","article-title":"Architecture of ribonucleoprotein complexes in influenza A virus particles.","volume":"439","author":"Noda","year":"2006","journal-title":"Nature"},{"key":"B24","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1016\/j.antiviral.2018.10.008","article-title":"In vitro characterization of baloxavir acid, a first-in-class cap-dependent endonuclease inhibitor of the influenza virus polymerase PA subunit.","volume":"160","author":"Noshi","year":"2018","journal-title":"Antiviral Res."},{"key":"B25","doi-asserted-by":"publisher","first-page":"10039","DOI":"10.1128\/JVI.00586-14","article-title":"Influenza A virus hemagglutinin and neuraminidase mutually accelerate their apical targeting through clustering of lipid rafts.","volume":"88","author":"Ohkura","year":"2014","journal-title":"J. Virol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"9633","DOI":"10.1038\/s41598-018-27890-4","article-title":"Characterization of influenza virus variants induced by treatment with the endonuclease inhibitor baloxavir marboxil.","volume":"8","author":"Omoto","year":"2018","journal-title":"Sci. Rep."},{"key":"B27","doi-asserted-by":"publisher","first-page":"5339","DOI":"10.1016\/j.vaccine.2013.09.013","article-title":"Influenza cost and cost-effectiveness studies globally\u2013a review.","volume":"31","author":"Peasah","year":"2013","journal-title":"Vaccine"},{"key":"B28","doi-asserted-by":"publisher","first-page":"5202","DOI":"10.1128\/AAC.00649-13","article-title":"Mechanism of action of T-705 ribosyl triphosphate against influenza virus RNA polymerase.","volume":"57","author":"Sangawa","year":"2013","journal-title":"Antimicrob. Agents Chemother."},{"key":"B29","first-page":"2867","article-title":"Inhibition of purine nucleotide metabolism by 6-methylthiopurine ribonucleoside and structurally related compounds.","volume":"33","author":"Shantz","year":"1973","journal-title":"Cancer Res."},{"key":"B30","doi-asserted-by":"publisher","first-page":"705","DOI":"10.1126\/science.177.4050.705","article-title":"Broad-spectrum antiviral activity of virazole: 1-f8- D-ribofuranosyl- 1,2,4-triazole- 3-carboxamide.","volume":"177","author":"Sidwell","year":"1972","journal-title":"Science"},{"key":"B31","doi-asserted-by":"publisher","first-page":"743","DOI":"10.1128\/AAC.45.3.743-748.2001","article-title":"Cyclopentane neuraminidase inhibitors with potent in vitro anti-influenza virus activities.","volume":"45","author":"Smee","year":"2001","journal-title":"Antimicrob. Agents Chemother."},{"key":"B32","first-page":"297","article-title":"Antiviral effect of formycin derivatives.","volume":"20","author":"Takeuchi","year":"1967","journal-title":"J. Antibiot."},{"key":"B33","first-page":"286","article-title":"Antiviral effect of formycin and formycin B.","volume":"19","author":"Takeuchi","year":"1966","journal-title":"J. Antibiot."},{"key":"B34","doi-asserted-by":"publisher","first-page":"823","DOI":"10.1016\/j.micinf.2005.10.005","article-title":"Association of functional influenza viral proteins and RNAs with nuclear chromatin and sub-chromatin structure.","volume":"8","author":"Takizawa","year":"2006","journal-title":"Microbes Infect."},{"key":"B35","doi-asserted-by":"publisher","first-page":"6679","DOI":"10.1128\/AAC.01156-16","article-title":"Distinct Effects of T-705 (Favipiravir) and ribavirin on influenza virus replication and Viral RNA Synthesis.","volume":"60","author":"Vanderlinden","year":"2016","journal-title":"Antimicrob. Agents Chemother."},{"key":"B36","doi-asserted-by":"publisher","first-page":"418","DOI":"10.1038\/363418a0","article-title":"Rational design of potent sialidase-based inhibitors of influenza virus replication.","volume":"363","author":"von Itzstein","year":"1993","journal-title":"Nature"},{"key":"B37","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1038\/nature17180","article-title":"Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys.","volume":"531","author":"Warren","year":"2016","journal-title":"Nature"},{"key":"B38","doi-asserted-by":"publisher","first-page":"780","DOI":"10.3390\/v13050780","article-title":"Influenza virus RNA synthesis and the innate immune response.","volume":"13","author":"Weis","year":"2021","journal-title":"Viruses"},{"key":"B39","doi-asserted-by":"publisher","first-page":"579","DOI":"10.1056\/NEJM196909112811102","article-title":"Therapeutic efficacy of amantadine HCl and rimantadine HCl in naturally occurring influenza A2 respiratory illness in man.","volume":"281","author":"Wingfield","year":"1969","journal-title":"N. Engl. J. Med."},{"journal-title":"Influenza (Seasonal).","year":"2014","key":"B40"},{"journal-title":"Summary of Neuraminidase (NA) Amino Acid Substitutions Associated with Reduced Inhibition by Neuraminidase Inhibitors (NAIs).","year":"2020","key":"B41"},{"key":"B42","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/0166-3542(85)90013-0","article-title":"Effect of ribavirin triphosphate on primer generation and elongation during influenza virus transcription in vitro.","volume":"5","author":"Wray","year":"","journal-title":"Antiviral Res."},{"key":"B43","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/0166-3542(85)90012-9","article-title":"Mode of action of ribavirin: effect of nucleotide pool alterations on influenza virus ribonucleoprotein synthesis.","volume":"5","author":"Wray","year":"","journal-title":"Antiviral Res."},{"key":"B44","doi-asserted-by":"publisher","first-page":"11151","DOI":"10.1016\/s0021-9258(19)38570-9","article-title":"Reconstitution of influenza virus RNA-nucleoprotein complexes structurally resembling native viral ribonucleoprotein cores.","volume":"265","author":"Yamanaka","year":"1990","journal-title":"J. Biol. Chem."},{"key":"B45","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1128\/AAC.00333-08","article-title":"CS-8958, a prodrug of the new neuraminidase inhibitor R-125489, shows long-acting anti-influenza virus activity.","volume":"53","author":"Yamashita","year":"2009","journal-title":"Antimicrob. Agents Chemother."}],"container-title":["Frontiers in Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2022.802671\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,18]],"date-time":"2022-02-18T04:34:36Z","timestamp":1645158876000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2022.802671\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,18]]},"references-count":45,"alternative-id":["10.3389\/fmicb.2022.802671"],"URL":"https:\/\/doi.org\/10.3389\/fmicb.2022.802671","relation":{},"ISSN":["1664-302X"],"issn-type":[{"type":"electronic","value":"1664-302X"}],"subject":[],"published":{"date-parts":[[2022,2,18]]},"article-number":"802671"}}